Abstract
Evidence suggests that astrocytes are not merely supportive cells in the nervous system but may actively participate in the control of neural circuits underlying cognition and behavior. In this study, we examined the role of astrocytes within the motor circuitry of the mammalian spinal cord. Pharmacogenetic manipulation of astrocytic activity in isolated spinal cord preparations obtained from neonatal mice revealed astrocyte-derived, adenosinergic modulation of the frequency of rhythmic output generated by the locomotor central pattern generator (CPG) network. Live Ca2+ imaging demonstrated increased activity in astrocytes during locomotor-related output and in response to the direct stimulation of spinal neurons. Finally, astrocytes were found to respond to neuronally-derived glutamate in a metabotropic glutamate receptor 5 (mGluR5) dependent manner, which in turn drives astrocytic modulation of the locomotor network. Our work identifies bi-directional signaling mechanisms between neurons and astrocytes underlying modulatory feedback control of motor circuits, which may act to constrain network output within optimal ranges for movement.
Highlights
Astrocytes, one of the predominant forms of glial cells in the nervous system, are a diverse and multifunctional group of cells with the capacity to integrate numerous neuronal-derived signals and modulate neuronal activity at a network level (Verkhratsky and Butt, 2013)
Hemisected spinal cords were prepared from neonatal (P6–8) GFAP::Cre;GCAMP6s mice to enable the visualization of gray matter astrocytes, broadly in laminae VII, VIII and X, whilst simultaneously recording fictive locomotor output via lumbar segment roots (L1–3; depicted in the schematic of Figure 1A)
We have used pharmacogenetic manipulation of astrocytes to show that astrocytes actively modulate spinal cord motor circuitry
Summary
Astrocytes, one of the predominant forms of glial cells in the nervous system, are a diverse and multifunctional group of cells with the capacity to integrate numerous neuronal-derived signals and modulate neuronal activity at a network level (Verkhratsky and Butt, 2013). Astrocytes are implicated in the control of rhythmic behaviors, such as respiration (Gourine et al, 2010; Huxtable et al, 2010; Sheikhbahaei et al, 2018), mastication (Morquette et al, 2015), feeding (Yang et al, 2015; Sweeney et al, 2016) and locomotion (Acton and Miles, 2015, 2017; Witts et al, 2015; Acton et al, 2018) These rhythmic motor behaviors are generated by a dedicated central pattern generator (CPG) networks. Neurons have traditionally been considered the primary, if not sole, source of such modulation, a growing body of evidence supports important roles for astrocytes in the modulation of CPG networks (Gourine et al, 2010; Acton and Miles, 2015; Morquette et al, 2015; Yang et al, 2015)
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